Growth factor signaling pathways can become activated as a consequence of inappropriate ligand expression and receptor mutation, or overexpression. This activation of signaling pathways, which in most cases are normally used for the development or growth of tissues, can contribute to the formation or progression of cancers. Some of the many receptor tyrosine kinases have been shown to have a functional role in human breast cancer. This laboratory is currently focusing on three major projects related to receptor tyrosine kinases and breast cancer: 1) IGF-I levels as a predictor of mammographic density and breast cancer in human females, 2) ectopic heregulin as it relates to the heterodimerization and activation of ErbB-2/ErbB-3 and 3) proliferative, pathological lesions produced by estrogen in the ACI rat that mimic the lesions seen in the human female. Our first project used selected mutant mice that would experimentally address the relative importance of tissue vs. serum IGF-I in determining the mammary branching phenotype. This is important because earlier studies had shown that elevated circulating IGF-I levels were associated with an increase in mammographic density, which is a strong predictor of breast cancer in human females. Our second project, we are investigating the proclivity of mouse mammary tumor cells to express heregulin, the ligand for ErbB-3 or ErbB-4. ErbB-2 has no known ligand, but it can heterodimerize with ErbB-3 in the presence of the heregulin ligand. ErbB-2 and ErbB-3 are commonly found in human breast cancer lines and can, when activated, stimulate cell proliferation and metastasis. The major objectives of this study is to determine whether coexpression (ectopic) of heregulin is a common feature of breast cancer cells in vivo, and if so, to determine if this property accounts for the activation of ErbB-2 and ErbB-3. Our third project deals with the proliferative and pathological lesions can be produced in the mammary gland of some rodents exposed to sex steroids. These lesions resemble those observed in the human breast that are considered to represent the progressive stages that result in invasive breast carcinomas. The presence of dysplastic cell hyperplasias in human breast tissue increases the relative risk of developing invasive breast cancer by 4-6 fold when compared to that of the normal epithelium. In our experiments, we examine estrogen-induced dysplastic cells of the ACI rat mammary gland for expression of genes associated with neoplastic progression or poor clinical outcome.